THE PRIOR ART AND ITS COMPARISON TO CLAIM 1 ..........................................19

A. SUBLINGUAL FORMULATION COMPRISING DISCRETE LIQUID
DROPLETS ...........................................................................................................................19
B. OF AN EFFECTIVE AMOUNT OF FENTANYL OR A FENTANYL
DERIVATIVE SELECTED FROM THE GROUP CONSISTING OF
SUFENTANIL, CARFENTANIL, LOFENTANIL AND ALFATENIL, A FREE
BASE OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, ......................20
C. IN A PHARMACEUTICALLY ACCEPTABLE LIQUID CARRIER ................................20

ii

U.S. Patent No. 8,835,460
D. SAID DROPLETS HAVING A MEAN DIAMETER OF FROM ABOUT 30 TO
ABOUT 70 MICRONS ..........................................................................................................21
3.

THE PRIOR ART AND ITS COMPARISON TO CLAIM 4 ..........................................22

A. A MULTI-DOSE DEVICE FOR SUBLINGUAL ADMINISTRATION OF A
DRUG .....................................................................................................................................23
B. A RESERVOIR CONTAINING THE LIQUID FORMULATION ....................................23
C. COMPRISING FENTANYL, OR A FENTANYL DERIVATIVE SELECTED
FROM THE GROUP CONSISTING OF SUFENTANIL, CARFENTANIL,
LOFENTANIL AND ALFATENIL, A FREE BASE OR A
PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, ...........................................23
D. IN A PHARMACEUTICALLY ACCEPTABLE LIQUID CARRIER; ...............................24
E. THE DEVICE HAVING AN ACTUATOR ..........................................................................24
F. WHICH WHEN ACTUATED DELIVERS A THERAPEUTICALLY
EFFECTIVE DOSE OF THE LIQUID FORMULATION ................................................24
G. IN THE FORM OF LIQUID DROPLETS ..........................................................................24
H. HAVING A MEAN DIAMETER OF FROM ABOUT 30 TO ABOUT 70
MICRONS..............................................................................................................................25
5.

U.S. Patent No. 8,835,460
B. COMPRISING DISCRETE LIQUID DROPLETS ..............................................................30
C. OF AN EFFECTIVE AMOUNT OF FENTANYL A FREE BASE OR A
PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, ...........................................30
D. A PHARMACEUTICALLY ACCEPTABLE LIQUID CARRIER .....................................31
E. WHEREIN THE SUBLINGUAL FENTANYL FORMULATION COMPRISES:
FROM ABOUT 0.001% TO ABOUT 15% BY WEIGHT OF FENTANYL FREE
BASE ......................................................................................................................................31
F. THE SUBLINGUAL FENTANYL FORMULATION COMPRISES … FROM
ABOUT 50% TO ABOUT 60% BY WEIGHT OF ETHANOL ...........................................31
G. THE SUBLINGUAL FENTANYL FORMULATION COMPRISES … FROM
ABOUT 4% TO ABOUT 6% BY WEIGHT OF PROPYLENE GLYCOL..........................32
H. SAID DROPLETS HAVING A MEAN DIAMETER OF AT LEAST ABOUT 10
MICRONS..............................................................................................................................35
3.

THE PRIOR ART AND ITS COMPARISON TO CLAIM 3 ..........................................36

A. A NON-PROPELLANT SUBLINGUAL FENTANYL FORMULATION .........................36
B. COMPRISING DISCRETE LIQUID DROPLETS ..............................................................37
C. OF AN EFFECTIVE AMOUNT OF FENTANYL A FREE BASE OR A
PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, ...........................................37
D. A PHARMACEUTICALLY ACCEPTABLE LIQUID CARRIER .....................................37
E. WHEREIN THE SUBLINGUAL FENTANYL FORMULATION CONSISTS
ESSENTIALLY OF: FROM ABOUT 0.001% TO ABOUT 15% BY WEIGHT OF
FENTANYL FREE BASE ....................................................................................................37
F. THE SUBLINGUAL FENTANYL FORMULATION CONSISTS ESSENTIALLY
OF … FROM ABOUT 50% TO ABOUT 60% BY WEIGHT OF ETHANOL...................37
G. THE SUBLINGUAL FENTANYL FORMULATION CONSISTS ESSENTIALLY
OF … FROM ABOUT 1% TO ABOUT 30% BY WEIGHT OF PROPYLENE
GLYCOL ................................................................................................................................38
H. SAID DROPLETS HAVING A MEAN DIAMETER OF AT LEAST ABOUT 10
MICRONS..............................................................................................................................40
C. GROUND 3 -- CLAIMS 1, 4 AND 5 ARE UNPATENTABLE AS OBVIOUS
OVER ROSS_GB, IN VIEW OF THE ’150 PATENT .....................................................40
iv

THE PRIOR ART AND ITS COMPARISON TO CLAIM 1 ..........................................41

A. SUBLINGUAL FORMULATION COMPRISING DISCRETE LIQUID
DROPLETS ...........................................................................................................................41
B. OF AN EFFECTIVE AMOUNT OF FENTANYL OR A FENTANYL
DERIVATIVE SELECTED FROM THE GROUP CONSISTING OF
SUFENTANIL, CARFENTANIL, LOFENTANIL AND ALFATENIL, A FREE
BASE OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, ......................41
C. IN A PHARMACEUTICALLY ACCEPTABLE LIQUID CARRIER ................................41
D. SAID DROPLETS HAVING A MEAN DIAMETER OF FROM ABOUT 30 TO
ABOUT 70 MICRONS ..........................................................................................................41
3.

THE PRIOR ART AND ITS COMPARISON TO CLAIM 4 ..........................................43

A. A MULTI-DOSE DEVICE FOR SUBLINGUAL ADMINISTRATION OF A
DRUG .....................................................................................................................................43
B. A RESERVOIR CONTAINING THE LIQUID FORMULATION ....................................44
C. COMPRISING FENTANYL, OR A FENTANYL DERIVATIVE SELECTED
FROM THE GROUP CONSISTING OF SUFENTANIL, CARFENTANIL,
LOFENTANIL AND ALFATENIL, A FREE BASE OR A
PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, ...........................................44
D. IN A PHARMACEUTICALLY ACCEPTABLE LIQUID CARRIER; ...............................44
E. THE DEVICE HAVING AN ACTUATOR ..........................................................................44
F. WHICH WHEN ACTUATED DELIVERS A THERAPEUTICALLY
EFFECTIVE DOSE OF THE LIQUID FORMULATION ................................................44
G. IN THE FORM OF LIQUID DROPLETS ..........................................................................44
H. HAVING A MEAN DIAMETER OF FROM ABOUT 30 TO ABOUT 70
MICRONS..............................................................................................................................44
5.

SUBLINGUALLY ADMINISTERING AN EFFECTIVE AMOUNT OF THE
SUBLINGUAL FORMULATION ACCORDING TO CLAIM 1 ........................................45

C. TO A HUMAN PATIENT EXPERIENCING PAIN. ..........................................................45
D. GROUND 4 -- CLAIMS 2 AND 3 ARE UNPATENTABLE AS OBVIOUS
OVER ROSS_GB, IN VIEW OF THE ‘862 PATENT, AND THE ‘150
PATENT. ...............................................................................................................................45
1.

THE PRIOR ART AND ITS COMPARISON TO CLAIM 2 ..........................................47

A. A NON-PROPELLANT SUBLINGUAL FENTANYL FORMULATION .........................47
B. COMPRISING DISCRETE LIQUID DROPLETS ..............................................................47
C. OF AN EFFECTIVE AMOUNT OF FENTANYL A FREE BASE OR A
PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, ...........................................47
D. A PHARMACEUTICALLY ACCEPTABLE LIQUID CARRIER .....................................47
E. WHEREIN THE SUBLINGUAL FENTANYL FORMULATION COMPRISES:
FROM ABOUT 0.001% TO ABOUT 15% BY WEIGHT OF FENTANYL FREE
BASE ......................................................................................................................................47
F. THE SUBLINGUAL FENTANYL FORMULATION COMPRISES … FROM
ABOUT 50% TO ABOUT 60% BY WEIGHT OF ETHANOL ...........................................48
G. THE SUBLINGUAL FENTANYL FORMULATION COMPRISES … FROM
ABOUT 4% TO ABOUT 6% BY WEIGHT OF PROPYLENE GLYCOL..........................48
H. SAID DROPLETS HAVING A MEAN DIAMETER OF AT LEAST ABOUT 10
MICRONS..............................................................................................................................48
3.

U.S. Patent No. 8,835,460
E. WHEREIN THE SUBLINGUAL FENTANYL FORMULATION CONSISTS
ESSENTIALLY OF: FROM ABOUT 0.001% TO ABOUT 15% BY WEIGHT OF
FENTANYL FREE BASE ....................................................................................................50
F. THE SUBLINGUAL FENTANYL FORMULATION CONSISTS ESSENTIALLY
OF … FROM ABOUT 50% TO ABOUT 60% BY WEIGHT OF ETHANOL...................50
G. THE SUBLINGUAL FENTANYL FORMULATION CONSISTS ESSENTIALLY
OF … FROM ABOUT 1% TO ABOUT 30% BY WEIGHT OF PROPYLENE
GLYCOL ................................................................................................................................51
H. SAID DROPLETS HAVING A MEAN DIAMETER OF AT LEAST ABOUT 10
MICRONS..............................................................................................................................51
VI. CLAIMS 1, 4 AND 5 ARE ANTICIPATED ......................................................................51
A.

THE PRIOR ART AND ITS COMPARISON TO CLAIM 1 ..........................................52

A. SUBLINGUAL FORMULATION COMPRISING DISCRETE LIQUID
DROPLETS ...........................................................................................................................52
B. OF AN EFFECTIVE AMOUNT OF FENTANYL OR A FENTANYL
DERIVATIVE SELECTED FROM THE GROUP CONSISTING OF
SUFENTANIL, CARFENTANIL, LOFENTANIL AND ALFATENIL, A FREE
BASE OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, ......................53
C. IN A PHARMACEUTICALLY ACCEPTABLE LIQUID CARRIER ................................53
D. SAID DROPLETS HAVING A MEAN DIAMETER OF FROM ABOUT 30 TO
ABOUT 70 MICRONS ..........................................................................................................54
3.

THE PRIOR ART AND ITS COMPARISON TO CLAIM 4 ..........................................55

A. A MULTI-DOSE DEVICE FOR SUBLINGUAL ADMINISTRATION OF A
DRUG .....................................................................................................................................55
B. A RESERVOIR CONTAINING THE LIQUID FORMULATION ....................................56
C. COMPRISING FENTANYL, OR A FENTANYL DERIVATIVE SELECTED
FROM THE GROUP CONSISTING OF SUFENTANIL, CARFENTANIL,
LOFENTANIL AND ALFATENIL, A FREE BASE OR A
PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, ...........................................56
vii

U.S. Patent No. 8,835,460
D. IN A PHARMACEUTICALLY ACCEPTABLE LIQUID CARRIER; ...............................56
E. THE DEVICE HAVING AN ACTUATOR ..........................................................................57
F. WHICH WHEN ACTUATED DELIVERS A THERAPEUTICALLY
EFFECTIVE DOSE OF THE LIQUID FORMULATION ................................................57
G. IN THE FORM OF LIQUID DROPLETS ..........................................................................57
H. HAVING A MEAN DIAMETER OF FROM ABOUT 30 TO ABOUT 70
MICRONS..............................................................................................................................58
5.

company. HCMF is a limited partnership. HCM is the general partner and
investment manager of Credes and HCMF. HCM is the investment manager of
HOF. HOM is the administrative general partner of Credes and HCMF. HI is the
general partner of HCM. J Kyle Bass is the sole member of HI and sole shareholder
of HOM. CFAD, Credes, HOF and HCMF act, directly or indirectly, through HCM
as the general partner and/or investment manager of Credes, HOF and HCMF. nXnP
is a paid consultant to HCM. Erich Spangenberg is the Manager and majority
member of nXnP. IPNav is a paid consultant to nXnP. Erich Spangenberg is the
Manager and majority member of IPNav. Other than HCM and J Kyle Bass in his
capacity as the Chief Investment Officer of HCM and nXnP and Erich Spangenberg
in his capacity as the Manager/CEO of nXnP, no other person (including any
investor, limited partner, or member or any other person in any of CFAD, Credes,
HOF, HCMF, HCM, HOM, HI, nXnP or IPNav) has authority to direct or control (i)
the timing of, filing of, content of, or any decisions or other activities relating to this
Petition or (ii) any timing, future filings, content of, or any decisions or other
activities relating to the future proceedings related to this Petition. All of the costs
associated with this Petition will be borne by HCM, CFAD, Credes, HOF and/or
HCMF.
NOTICE OF RELATED MATTERS
Petitioner is aware of a concurrently filed Petition for inter partes review

2

U.S. Patent No. 8,835,460

(“IPR”) of U.S. Patent No. 8,486,972, upon which the ‘460 patent claims priority
as a divisional patent application (Case No. Unassigned); and a concurrently
filed Petition for IPR of U.S. Patent No. 8,835,459 (Case No. Unassigned). To
the best of Petitioner’s knowledge, there are no pending litigations or other
related matters related to the ’460 patent that would affect, or be affected by, a
decision in this proceeding.
NOTICE OF SERVICE INFORMATION
Please address all correspondence to the lead and backup counsel at the
address shown above. Petitioner also consents to electronic service by e-mail at:
gonsalves@gonsalveslawfirm.com and chris@miplaw.com.
GROUNDS FOR STANDING
Petitioner certifies that the patent for which review is sought is available for
inter partes review, and that Petitioner is not barred or estopped from requesting an
inter partes review on the grounds identified in the petition.
STATEMENT OF PRECISE RELIEF REQUESTED
Petitioner relies on the following patents and printed publications to support
its grounds of challenge to claims 1-5 of the ‘460 patent in this Petition:
1. Great Britain patent publication GB2399286A by Calvin John Ross et al,
entitled “Sub-lingual fentanyl formulation.” published September 15, 2004
(“Ross_GB,” Exhibit 1003). Ross_GB is prior art to the ‘460 patent under
3

U.S. Patent No. 8,835,460

at least 35 U.S.C. § 102(b) (pre-AIA) because it was published on
September 15, 2004, more than one year prior to January 25, 2006, the
earliest effective filing date for the claims of the ‘460 patent.
2. United States Patent 5,370,862 by Karin Klokkers-Bethke et al., entitled
“Pharmaceutical hydrophilic spray containing nitroglycerin for treating
angina,” issued December 6, 1994 (“the ‘862 patent,” Exhibit 1004). The
‘862 patent is prior art to the ‘460 patent under at least 35 U.S.C. § 102(b)
(pre-AIA) because it issued on December 6, 1994, more than one year prior
to January 25, 2006, the earliest effective filing date for the claims of the
‘460 patent.
3. United States Patent Publication 2002/0055496 by Randall McCoy et al.
entitled “Formulation and System For Intra-oral Delivery Of Pharmaceutical
Agents,” published May 9, 2002 (“the ‘496 publication,” Exhibit 1005). The
‘496 publication is prior art to the ‘460 patent under at least 35 U.S.C. §
102(b) (pre-AIA) because it was published on May 9, 2002, more than one
year prior to January 25, 2006, the earliest effective filing date for the
claims of the ‘460 patent.
4. United States Patent 6,946,150 by Brian Whittle entitled “Pharmaceutical
formulation” issued September 20, 2005 (“the ‘150 patent,” Exhibit 1007).
The ‘150 patent is prior art to the ‘460 patent under at least 35 U.S.C. §

4

U.S. Patent No. 8,835,460

102(a) (pre-AIA) because it was patented on September 20, 2005 in this
country, before January 25, 2006, the earliest effective filing date for the
claims of the ‘460 patent.
Petitioner requests that claims 1-5 of the '460 patent be held unpatentable
based on the following grounds:
Ground 1. Claims 1, 4, and 5 are unpatentable as obvious over Ross_GB1,
in view of the ’496 publication. The ‘496 publication was not cited by the
Examiner as basis for rejection during the prosecution of the application that led
to the ‘460 patent. See 35 U.S.C. § 103(a).2
Ground 2. Claims 2 and 3 are unpatentable as obvious over Ross_GB, in
view of the ‘496 publication and the ‘862 patent. The ‘496 publication was not
cited by the Examiner as basis for rejection during the prosecution of the
application that led to the ‘460 patent and the ‘862 patent was not before the
1

Ross_GB is a foreign priority document US2006/0062812, which was the cited

by the examiner during the prosecution of the application that led to the ‘460
patent.
2

The pre-AIA version of § 103 applies in this proceeding, because the ‘460 Patent

has an effective filing and issue date before March 16, 2013. The ‘460 patent
claims a priority date of January 25, 2006.

5

U.S. Patent No. 8,835,460

Examiner during the prosecution of the application that led to the ‘460 patent. See
35 U.S.C. § 103(a).
Ground 3. Claims 1, 4 and 5 are unpatentable as obvious over Ross_GB, in
view of the ‘150 patent. See 35 U.S.C. § 103(a).
Ground 4. Claims 2 and 3 are unpatentable as obvious over Ross_GB, in
view of the ‘862 patent and the ‘150 patent. See 35 U.S.C. § 103(a).
Ground 5. Claims 1, 4, and 5 are unpatentable as anticipated by the ’496
publication. See 35 U.S.C. § 102(b).
THRESHOLD REQUIREMENT FOR INT ER PAR T ES REVIEW
A petition for inter partes review must demonstrate "a reasonable
likelihood that the petitioner would prevail with respect to at least one of the
claims challenged in the petition." 35 U.S.C. § 314(a). This Petition meets that
threshold. All of the elements of claims 1-5 of the '460 Patent are taught or
suggested in the prior art, as explained below in the proposed grounds of
unpatentability. The reasons to combine the cited references, where applicable,
are established under 35 U.S.C. § 103(a).

INTRODUCTION AND SUMMARY OF ARGUMENT
The ‘460 patent is directed to a sublingual liquid fentanyl formulation, a

multi-dose device for administering a sublingual liquid fentanyl formulation, and a
method of treating pain using the sublingual liquid fentanyl formulation. The
recited elements were well known in the art at the time of the invention and each
element of the claims is clearly taught by prior art references, alone and in
combination. Further the combination of references would have been obvious to a
person of ordinary skill in the art. No evidence or arguments of unexpected results
or advantages were advanced during the prosecution of the ‘460 patent.
Accordingly, the claims of the ‘460 patent are anticipated by or obvious over the
prior art.
The public has a significant interest in ensuring monopoly privileges are not
granted by an invalid patent particularly where, as here, Subsys® (the drug
corresponding to the ‘460 patent) can cost up to $300 per day per patient. 3 The
3

patent owner can attempt to secure such high prices through FDA regulatory
exclusivity but should not be allowed to extend these privileges with an obvious
‘460 patent.
II.

THE ‘460 PATENT AND PROSECUTION HISTORY OF THE '460
PATENT
A.

The '460 Patent

The ‘460 patent is directed to sublingual fentanyl formulations, a multi-dose
device for administering a sublingual fentanyl formulation, and a method of
treating pain using the sublingual fentanyl formulation. The common feature of
the four independent claims is that each recites a fentanyl formulation comprising
discrete liquid droplets (claims 1, 2 and 3) or a multi-dose device capable of
delivering a fentanyl formulation in the form of liquid droplets (claim 4). The
discrete liquid droplets have a mean diameter of from about 30 to about 70 microns
in independent claims 1 and 4 and at least about 10 microns in independent claims
2 and 3. In addition, independent claims 2 and 3 recite specific amounts by weight
of fentanyl, ethanol and propylene glycol.

8

U.S. Patent No. 8,835,460

The sublingual formulation of the independent claims (except for claim 1)
contains three recited components: fentanyl4; ethanol; and propylene glycol.
Fentanyl is a μ-opioid receptor agonist with analgesic potency approximately 80100 times that of morphine. See ‘460 patent 1:13-14. (Exh. 1001). Ethanol and
propylene glycol are both identified as organic solvents which are used to enhance
the solubility of fentanyl. Id. at 11: 22-29. (Exh. 1001).
In the prior art, fentanyl is administered by way of a number of different
routes including oral, parenteral, buccal, transdermal Id. at 1:30-34. (Exh. 1001).
and intranasal. See. U.S. Patent No. 8,889,176 (the ‘176 patent) 2:10-16. (Exh.
1006). Orally administered fentanyl is subject to first pass effect metabolism,
which leaves 50% or more of the fentanyl unabsorbed. See the ‘460 patent 1:3031. (Exh. 1001).The other forms of administration avoid or decrease the first pass
effect for fentanyl. Id. at 1:32-34. (Exh. 1001).
Transdermal administration of fentanyl is reportedly not suitable for severe
pain or breakthrough pain. See. ‘176 patent 1:58-64. (Exh. 1006). Buccal
administration of fentanyl via transmucosal lozenge is reported to have relatively
slow absorption times. Id. at 1:58-64. (Exh. 1006). However, sublingual spray
4

The claims of the ‘460 patent recite various forms of fentanyl and fentanyl

derivatives, which are referred to as “fentanyl” unless otherwise noted.

9

U.S. Patent No. 8,835,460

administration of fentanyl that is free of propellant is reported to provide rapid
onset of therapeutic effect. See Ross_GB p. 3, ll. 29-33. (Exh. 1003) In addition,
oral transmucosal administration of fentanyl is reported as providing rapid onset of
effect in as low as 5 minutes after dosing.5
B.

The Prosecution History Of The '460 Patent

The ‘460 patent was filed on May 15, 2013 as a continuation of Application
No. 11/689,739 (now patent No. 8,486,972), which claims benefit of U.S.
provisional application No. 60/763,057 filed on January 25, 2006. The ‘460 patent
was filed with 4 original claims.
The claims were subject to a Restriction dated November 21, 2013, to which
the Applicant elected to prosecute claims 1 and 4 drawn to a fentanyl formulation
without traverse. See 12/17/2013 Response. (Exh. 1017). Original claim 1 is
reproduced below:
1. (Original) A sublingual fentanyl formulation comprising discrete liquid
droplets of an effective amount of fentanyl, a free base or a pharmaceutically
acceptable salt thereof, or derivative thereof, in a pharmaceutically

acceptable liquid carrier; said droplets having a mean diameter of at least
about 10 microns.
A Non-Final Office Action issued on January 10, 2014 (Exh. 1018) rejecting
the claims under 35 U.S.C. § 102/103 over three references: 1) McCarty (US
2007/0071806); 2) Ross (US 2003/0190290); and 3) Ross (US 2006/0062812). In
addition several rejections were made for nonstatutory obviousness-type double
patenting including over claims 1-3 of the parent case, US Patent No. 8,486,972.
See 01/10/2014 Rejection (Exh. 1018).
Applicants filed an Amendment dated March 6, 2014 making no
amendments to the claims and primarily arguing that none of the cited references
teach the specific droplet size recited in the claims, i.e. discrete droplets having a
mean diameter of at least 10 microns. See 03/06/2014 Amendment. (Exh. 1019).
Applicants argued that none of the references “teach or suggest that a fentanyl
formulation of any particular droplet size would be useful for treating pain.” Id. at
p. 12- 13.
A second Non-Final Office Action issued on March 21, 2014 (Exh. 1020)
maintaining the 35 U.S.C. § 102/103 rejection over McCarty and withdrawing the
rejections over Ross_2003 and Ross_2006. The claims were also rejected as as
obvious over Ross_2003 in view of Whittle (U.S. Patent No. 6,946,150). Id.
Applicants submitted an Amendment dated April 15, 2014 (Exh. 1012).
This time Applicants amended independent claim 1 changing the droplet size from
11

U.S. Patent No. 8,835,460

“at least 10 microns” to “from about 30 to about 70 microns”. Id. at p. 2. The
amendment to independent Claim 4 left the droplet size unchanged (“at least 10
microns”) but amended the range of propylene glycol from “0.1% to about 40%”
to “4% to 6%”. Id. In addition, new claim 5 was added which was the same as unamended claim 4 but used the “consisting essentially of” transition phrase. Id. No
explanation was supplied for the support in the specification for the new claim.
Applicants again argued that McCarty did not disclose any particular droplet
size. With regard to Ross_2003 in view of Whittle, applicants again argued that
“None of the references in view Whittle teach a fentanyl . . . sublingual
formulation with a discrete liquid droplet having a mean diameter of from about 30
to about 70 microns.” Id. at p. 6. Applicants did not provide any explanation as to
why or even if the narrowed range of droplet mean diameter provided any benefit
over the broader range originally in the claims. With regard to new claim 5,
Applicants did not argue why, or even if, the transitional phrase “consisting
essentially of” was advantageous over the prior art.
Applicants filed a terminal disclaimer to obviate the double patenting
rejection over prior patents including the parent patent (the ‘972 patent) on April
24, 2014. See Terminal Disclaimer. (Exh. 1021).
A Notice of Allowance issued on May 6, 2014 (Exh. 1022) which rejoined
withdrawn claims 2 and 3 but did not provide reasons for allowance. Minor

12

U.S. Patent No. 8,835,460

Examiner’s Amendments were made non May 13, 2014 and June 19, 2014. The
‘460 patent issued on September 16, 2014. A Certificate of Correction was
requested by the Applicants and certified on November 25, 2014 (Exh. 1023) to
add a comma to claim 3 between “fentanyl” and “a free base” and to add a carriage
return.
It also appears that in the issued patent, New claim 5 was renumbered as
claim 3, Original claim 2 was renumbered as claim 5, Original claim 3 was
renumbered as 4, and Original claim 4 was renumbered as claim 2.
During the prosecution the Applicants argued that the cited references did
not teach or suggest the specific droplet diameter and/or the specific weight ratios
of the two recited solvents (ethanol and propylene glycol). See 04/15/2015
Amendment (Exh. 1012). Applicants did not include arguments of unexpected
results to overcome the obviousness rejection. As described herein however, the
claims would have been obvious to one of ordinary skill in the art in light of the
teachings of the references cited herein.
III.

CLAIM CONSTRUCTION
In inter partes review, a claim term is given its "broadest reasonable

The claim term “discrete liquid droplets” (or “liquid droplets”), which is
recited in claims 1-4, requires construction. The phrase is not explicitly defined in
the ‘460 specification, but is closely associated with the term “spray” throughout the
‘460 specification. For one example, the specification states, “[I]n certain
embodiments, the present invention is directed to a method of treating pain
comprising sublingually administering a liquid spray formulation in the form of
discrete liquid droplets having a mean diameter of at least about 10 microns, . . .”
See ‘460 patent 3:17-20. (Exh. 1001).
The term spray was defined prior to the alleged effective filing date of the
‘460 patent as “water or other liquid broken up into minute droplets and blown,
ejected into, or falling through the air.” 6 The phrase “discrete liquid droplet”
broadest reasonable construction must be construed as meaning, “water or other
liquid broken up into minute droplets and blown, ejected into, or falling through the
air.”
B.

The term “pharmaceutically acceptable liquid carrier”, which is recited in
claims 1-4, requires construction. The phrase is defined in the ‘460 specification by
way of examples:
“Pharmaceutically acceptable carriers include but are not limited to water,
buffer, saline, buffered saline, dextrose solution, propylene glycol,
polyethylene glycols, miglyol, and the like. In a specific embodiment, a
carrier that may be used in the pharmaceutical formulation of the present
invention is phosphate buffered saline, or a buffered saline. In certain
preferred embodiments the carrier is water.” See ‘460 patent 12:54-60 (Exh.
1001).
Further, the term “carrier” is defined by way of examples in the specification:
“Preferably the fentanyl, a pharmaceutically acceptable salt thereof, or
derivative thereof, is dissolved in an organic solvent. Examples of organic
solvents that may be used to enhance the solubility of fentanyl, or the
pharmaceutically acceptable salt thereof in a carrier such as e.g., water,
include for example and without limitation: lower alcohols (e.g. C14 alcohols)
8 alcohols

such as methanol, ethanol, propyl alcohol, or butyl alcohol; C2-

having two or three hydroxyl groups, preferably glycerol,

propylene glycol or butylene glycol; and polyethylene glycols such as
PEG200 and PEG400 and the like..” Id. at 11:20-29.
Accordingly, the term “pharmaceutically acceptable liquid carrier” includes,
but is not limited to, water. The specification specifically contemplates that organic
solvents can and will be dissolved in the water. Further, the specification

15

U.S. Patent No. 8,835,460

contemplates that the carrier may be a solvent without any water. The phrase
“pharmaceutically acceptable liquid carrier” broadest reasonable construction must
be construed as meaning, “water (including aqueous buffers and saline), one or
more organic solvents, or a mixture of both water and one or more organic
solvents”
C.

Claim 3 recites:
A non-propellant sublingual fentanyl formulation comprising discrete liquid
droplets of an effective amount of fentanyl a free base, or a pharmaceutically
acceptable salt thereof, in a pharmaceutically acceptable liquid carrier,
wherein the sublingual fentanyl formulation consists essentially of:
from about 0.001% to about 15% by weight fentanyl free base;
from about 50% to about 60% by weight of ethanol; and
from about 1% to about 30% by weight of propylene glycol;
said droplets having a mean diameter of at least about 10 microns.
The phrase, “wherein the sublingual fentanyl formulation consists essentially
of:” , which is in claim 3 only, requires construction. “The transitional phrase
“consisting essentially of” limits the scope of a claim to the specified materials or
steps “and those that do not materially affect the basic and novel characteristic(s)”
of the claimed invention.” M.P.E.P 2111.03 citing In re Herz, 537 F.2d 549, 55152, 190 USPQ 461, 463 (CCPA 1976) (emphasis in original). Issued Claim 3 was

16

U.S. Patent No. 8,835,460

added (as New Claim 5) in the last amendment in the prosecution history. See
04/15/2014 Response. (Exh. 1012). No support for the new claim was provided
and neither the claim nor the transition phrase was addressed by the Applicant or by
the Examiner during the prosecution. With regard to the claims with similar
limitations, during prosecution, Applicants argued that prior art did not teach the
specific ratio of ethanol and propylene glycol and the specific droplet diameter. Id.
at p.7.
Claim 3 is directed to a “non-propellant sublingual fentanyl formulation.” Of
note is that the transitional phrase appears after the recitation of the claim element
of “in a pharmaceutically acceptable liquid carrier.” Accordingly, the “consists
essentially of” transition phrase applies only to the components appearing after the
phrase, i.e., fentanyl free base, ethanol and propylene glycol. The phrase’s broadest
reasonable construction, therefore, must be construed as excluding any component
in the fentanyl formulation, not including the pharmaceutically acceptable liquid
carrier, that would interfere or prevent the fentanyl formulation from the formation
of droplets in the cited diameter range.
IV.

LEVEL OF SKILL IN THE ART
A person of ordinary skill in the art at the time of filing of these patents

would be someone who holds a B.S. degree in pharmacy, chemistry, engineering, or
related fields with several years of experience, or a Ph.D. degree in the same fields,

17

U.S. Patent No. 8,835,460

and is a highly trained formulation chemist, well-versed in developing formulations
from experience with drug formulations in an industrial or academic environment.
Park Decl. ¶ 9. (Exh. 1002).
V.

CLAIMS 1-5 ARE OBVIOUS
The obviousness inquiry is a question of law based on four factual

predicates: (1) "the scope and content of the prior art," (2) the "differences between
the prior art and the claims at issue," (3) "the level of ordinary skill in the pertinent
art," and (4) "secondary considerations" such as "commercial success, long felt but
unsolved needs, failure of others, etc." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398,
406-07 (2007) (citing Graham v. John Deere Co., 383 U.S. 1, 17-18 (1966)); 35
U.S.C. § 103(a). KSR reaffirmed that "[t]he combination of familiar elements
according to known methods is likely to be obvious when it does no more than
yield predictable results." KSR, 550 U.S. at 416.
"Motivation to combine may be found in many different places and forms."
Par Pharm. Inc. v. TWI Pharms., Inc., 773 F.3d 1186, No. 2014-1391, 2014 U.S.
App. LEXIS 22737, at *24 (Fed. Cir. Dec. 3, 2014) (citations omitted). Thus, for
example, a challenger is not limited to the same motivation that the patentee had.
Id. (citing Alcon Research, Ltd. v. Apotex Inc., 687 F.3d 1362, 1369 (Fed. Cir.
2012), cert denied, 133 S. Ct. 1736 (2013)).
A. Ground 1 -- Claims 1, 4 and 5 Are Unpatentable As Obvious Over
18

U.S. Patent No. 8,835,460

Ross_GB, In View Of The ’496 Publication
1.

Independent Claim 1

Claim 1 is directed to a sublingual formulation comprising discrete liquid
droplets of an effective amount of fentanyl . . . and a pharmaceutically
acceptable liquid carrier. The droplets have a mean diameter of from about 30
to about 70 microns.
2.

The Prior Art And Its Comparison To Claim 1

As explained in detail below, claim 1 would have been obvious to one of
ordinary skill in the art in light of the teachings of Ross_GB and the ‘496
publication. Park Decl. ¶ 15. (Exh. 1002).
a.

Ross_GB, Abstract (Exh. 1003). Ross_GB further teaches that its fentanyl
formulation is “preferably administered sublingually as a spray. The formulations
are well tolerated when administered to the sensitive sublingual mucosa and the
sublingual spray administration will result in rapid onset of the therapeutic effect of
the fentanyl.” Id. at p. 3, ll. 29-33 (emphasis added). Moreover, as explained by Dr.
Park, “one of ordinary skill in the art as of the alleged effective filing date of the
’460 patent (i.e., January 25, 2006) would have understood that the spray disclosed
in Ross_GB comprises discrete liquid droplets.” Park Decl. ¶ 16. (Exh. 1002). For
19

U.S. Patent No. 8,835,460

example, a spray was defined prior to the alleged effecting filing date of the ‘460
patent as having discrete liquid droplets: “water or other liquid broken up into
minute droplets and blown, ejected into, or falling through the air.”7
Accordingly, “the claimed ‘sublingual formulation comprising discrete liquid
droplets’ would have been obvious over the teachings of Ross_GB.” Park Decl. ¶
16. (Exh. 1002).
b.

of an effective amount of fentanyl or a fentanyl derivative selected from the
group consisting of sufentanil, carfentanil, lofentanil and alfatenil, a free
base or a pharmaceutically acceptable salt thereof,
Ross_GB teaches that “a therapeutically effective amount of a [fentanyl]

formulation for the treatment of pain according to the invention is used.”
Exh. 1003 at p. 8, ll. 10-11 (emphasis added).
c.

in a pharmaceutically acceptable liquid carrier
Ross_GB teaches that the dose of the fentanyl formulation includes water as

a pharmaceutically acceptable liquid carrier:
“(a) fentanyl or a pharmaceutically acceptable salt thereof;
(b) water as carrier; and
(c) a polar organic solvent in sufficient amount to enhance the
7

said droplets having a mean diameter of from about 30 to about 70 microns
Like Ross_GB, the ‘496 publication teaches a fentanyl formulation: “[t]wo

formulations containing fentanyl citrate were prepared...” See ‘496 publication, ¶
[0041] (Exh. 1005).
The ‘496 publication also teaches that its fentanyl formulation is
administered in liquid droplets “sized within the range of about 1 to 200 microns,
more preferably within the range of 10-100 microns.” Id. at ¶ [0019]. As explained
by Dr. Park, “[t]he preferred range of 10 to 100 microns encompasses the entire
claimed range of about 30 microns to about 70 microns recited in claim 1 of the
‘460 patent.” Park Decl. ¶ 21 (Exh. 1002). As further explained by Dr. Park,
“[w]hile the preferred range of the ‘496 publication is slightly broader than the
claimed range of about 30 to about 70 microns, the ‘460 patent does not identify or
suggest there is anything advantageous about the claimed range as compared to the
preferred range of the ‘496 publication..” Id. Accordingly “the claimed “said
droplets having a mean diameter of from about 30 to about 70 microns” would
have been obvious over the teachings of the ‘496 publication.” Id.
As further explained by Dr. Park, “[i]t would have been obvious to have a
fentanyl formulation with a discrete liquid droplet with a mean diameter of from
about 30 to about 70 microns in light of the teachings of Ross_GB and the ‘496
21

U.S. Patent No. 8,835,460

publication The ‘496 publication, like Ross_GB, teaches a fentanyl formulation.
The ‘496 publication also teaches “a decreased droplet size translates to a higher
surface area to be absorbed by the mucosa of the intra-oral cavity.” Id. at ¶22.
Accordingly, as indicated by Dr. Park, “one of ordinary skill in the art would have
been motivated to combine the teachings of the ‘496 publication with the teachings
of Ross_GB.” Id.
Moreover, as explained by Dr. Park, “[o]ne aspect of the administration of a
drug is to achieve a small droplet size so as to eliminate or decrease the discomfort
felt by a patient in receiving the drug.” Id. at ¶23. Accordingly, “[o]ne of ordinary
skill in the art would have been motivated to combine the fentanyl teachings of
Ross_GB with the small droplet size of the ‘496 publication to eliminate or
decrease any discomfort to the patient from administration of the drug.” Id.
3.

Independent Claim 4

Claim 4 is directed to a multi-dose device for sublingual administration of a
drug. The device comprises a reservoir containing a liquid formulation comprising
fentanyl . . .or a pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable liquid carrier. The device has an actuator which when actuated delivers
a therapeutically effective dose of the liquid formulation in the form of liquid
droplets having a mean diameter of from about 30 to about 70 microns.
4.

The Prior Art And Its Comparison To Claim 4
22

U.S. Patent No. 8,835,460

As explained in detail below, claim 4 would have been obvious to one of
ordinary skill in the art in light of the teachings of Ross_GB, and the ’496
publication. Park Decl. ¶ 24 (Exh. 1002).
a.

a multi-dose device for sublingual administration of a drug
Ross_GB teaches a “single or multiple use devices comprising a single or

a reservoir containing the liquid formulation
Ross_GB teaches, “Formulations according to the invention are preferably

packaged as a bulk solution containing multiple doses in a pump spray system
comprising a sealed container fitted with a metering pump. Thus as an aspect of the
invention we provide a sealed container containing a plurality of doses of a
formulation according to the invention.” Id. at p. 8, ll. 13-18.
c.

comprising fentanyl, or a fentanyl derivative selected from the group
consisting of sufentanil, carfentanil, lofentanil and alfatenil, a free base or
a pharmaceutically acceptable salt thereof,
Ross_GB teaches that “The invention relates to formulations of fentanyl,

in a pharmaceutically acceptable liquid carrier;
Ross_GB teaches that the dose of the fentanyl formulation includes water as

a pharmaceutically acceptable liquid carrier:
(a) fentanyl or a pharmaceutically acceptable salt thereof;
(b) water as carrier; and
(c) a polar organic solvent in sufficient amount to enhance the
solubility of the fentanyl or pharmaceutically acceptable salt thereof
in the water. Id. at page 3, ll. 21-27 (emphasis added).
e.

the device having an actuator
Ross_GB teaches that “Another aspect of the invention is a metered dose

dispensing system comprising a sealed container containing a formulation of the
invention fitted with a metering pump, an actuator and a channelling device.” Id.
at p. 9, ll. 4-6. (emphasis added).
f.

which when actuated delivers a therapeutically effective dose of the liquid
formulation
Ross_GB teaches, “Preferably the actuator will be designed to deliver a

in the form of liquid droplets
Ross_GB further teaches that its fentanyl formulation is “preferably

administered sublingually as a spray. The formulations are well tolerated when
administered to the sensitive sublingual mucosa and the sublingual spray
administration will result in rapid onset of the therapeutic effect of the fentanyl.” Id.

24

U.S. Patent No. 8,835,460

at p. 3, ll. 29-33 (emphasis added). Moreover, as explained by Dr. Park, “one of
ordinary skill in the art as of the alleged effective filing date of the ’460 patent (i.e.,
January 25, 2006) would have understood that the spray disclosed in Ross_GB
comprises discrete liquid droplets.” Park Decl. ¶ 16. (Exh. 1002). For example, a
spray was defined prior to the alleged effecting filing date of the ‘460 patent as
having discrete liquid droplets: “water or other liquid broken up into minute
droplets and blown, ejected into, or falling through the air.” Id.
Accordingly, “the claimed ‘sublingual formulation comprising discrete liquid
droplets’ would have been obvious over the teachings of Ross_GB.” Id.
h. having a mean diameter of from about 30 to about 70 microns

Like Ross_GB, the ‘496 publication teaches a fentanyl formulation: “[t]wo
formulations containing fentanyl citrate were prepared...” See ‘496 publication, ¶
[0041] (Exh. 1005).
The ‘496 publication also teaches that its fentanyl formulation is
administered in liquid droplets “sized within the range of about 1 to 200 microns,
more preferably within the range of 10-100 microns.” Id. at ¶ [0019]. As explained
by Dr. Park, “[t]he preferred range of 10 to 100 microns encompasses the entire
claimed range of about 30 microns to about 70 microns recited in claim 1 of the
‘460 patent.” Park Decl. ¶ 21 (Exh. 1002). As further explained by Dr. Park,
“while the preferred range of the ‘496 publication is slightly broader than the
25

U.S. Patent No. 8,835,460

claimed range of about 30 to about 70 microns, the ‘460 patent does not identify or
suggest there is anything advantageous about the claimed range as compared to the
preferred range of the ‘496 publication..” Id. Accordingly “the claimed ‘said
droplets having a mean diameter of from about 30 to about 70 microns’ would
have been obvious over the teachings of the ‘496 publication.” Id.
As further explained by Dr. Park, “[i]t would have been obvious to have a
fentanyl formulation with a discrete liquid droplet with a mean diameter of from
about 30 to about 70 microns in light of the teachings of Ross_GB and the ‘496
publication. The ‘496 publication, like Ross_GB, teaches a fentanyl formulation.
The ‘496 publication also teaches “a decreased droplet size translates to a higher
surface area to be absorbed by the mucosa of the intra-oral cavity.” Id. at ¶22.
Accordingly, as indicated by Dr. Park, “one of ordinary skill in the art would have
been motivated to combine the teachings of the ‘496 publication with the teachings
of Ross_GB.” Id.
Moreover, as explained by Dr. Park, “[o]ne aspect of the administration of a
drug is to achieve a small droplet size so as to eliminate or decrease the discomfort
felt by a patient in receiving the drug.” Id. at ¶23. Accordingly, “[o]ne of ordinary
skill in the art would have been motivated to combine the fentanyl teachings of
Ross_GB with the small droplet size of the ‘496 publication to eliminate or
decrease any discomfort to the patient from administration of the drug.” Id.

26

U.S. Patent No. 8,835,460

5.

Dependent Claim 5

Claim 5 depends from independent claim 1 and is directed to a method of
treating pain comprising sublingually administering an effective amount of the
sublingual formulation according to claim 1 to a human patient experiencing pain.
That is, claim 5 requires the same fentanyl sublingual formulation of claim 1 except
that it recites the method steps of administering an effective amount of the
formulation to a human patient experiencing pain.
6.

The Prior Art And Its Comparison To Claim 5

As explained in detail below, claim 5 would have been obvious to one of
ordinary skill in the art in light of the teachings of Ross_GB, and the ’496
publication. Park Decl. ¶ 33. (Exh. 1002).
a.

A method of treating pain comprising
Ross_GB teaches that, “Formulations of the invention are useful in analgesia

and in the treatment of pain.” Ross_GB, p. 8, l. 5. (Exh. 1003).
b.

sublingually administering an effective amount of the sublingual
formulation according to claim 1
The analysis of the sublingual formulation according to Claim 1 is provided

above at § IV.A.2.
Ross_GB teaches that “a therapeutically effective amount of a [fentanyl]
formulation for the treatment of pain according to the invention is used.” Id. at p. 8,
27

U.S. Patent No. 8,835,460

ll. 10-11 (emphasis added). Ross_GB further teaches that its fentanyl formulation
is “preferably administered sublingually as a spray. The formulations are well
tolerated when administered to the sensitive sublingual mucosa and the sublingual
spray administration will result in rapid onset of the therapeutic effect of the
fentanyl.” Id. at p. 3, ll. 29-33 (emphasis added).
c.

to a human patient experiencing pain.
Ross_GB teaches, “[f]entanyl is a narcotic alkaloid, which has been used for

many years as an anaesthetic and an analgesic, especially in the treatment of
moderate to severe pain.” Id. at p. 1, ll. 6-7. Ross_GB further teaches
administration of “formulations of fentanyl, especially pump spray formulations
suitable for sublingual delivery” (Ross_GB, page 1, ll. 3-4) and “the formulations
of the invention are preferably administered sublingually as a spray.” Id. at p. 3, ll.
29-30. Ross_GB further teaches “monitor[ing] patients for evidence of self
medication.” Id. at p. 1, ll. 15. As explained by Dr. Park, “[b]ecause only people
can self-medicate, the sublingual administration taught by Ross_GB is to a human,
as required by this claim limitation.” Park Decl. ¶ 37. (Exh. 1002).
B. Ground 2 -- Claims 2 And 3 Are Unpatentable As Obvious Over
Ross_GB, In View Of The ‘862 Patent, And The ‘496 Publication.
1.

Independent Claim 2

Claim 2 is directed to a non-propellant sublingual fentanyl formulation

28

U.S. Patent No. 8,835,460

comprising discrete liquid droplets of an effective amount of fentanyl . . . in a
pharmaceutically acceptable liquid carrier. The sublingual fentanyl formulation
comprises: from about 0.001% to about 15% by weight fentanyl free base; from
about 50% to about 60% by weight of ethanol; and from about 4% to about 6%
by weight of propylene glycol. The droplets have a mean diameter of at least
about 10 microns.
2.

The Prior Art And Its Comparison To Claim 2

As explained in detail below, claim 2 would have been obvious to one of
ordinary skill in the art in light of the teachings of Ross_GB, the ‘862 patent and the
‘496 publication. Park Decl., ¶ 38. (Exh. 1002).
a.

See Ross GB, Abstract (Exh. 1003). Ross_GB further teaches that its fentanyl
formulation is “preferably administered sublingually as a spray. The formulations
are well tolerated when administered to the sensitive sublingual mucosa and the
sublingual spray administration will result in rapid onset of the therapeutic effect of
the fentanyl.” Id. at p. 3, ll. 29-33 (emphasis added).
Further, Ross_GB further teaches that “[t]he [fentanyl] formulations of the
present invention are also preferably free of any propellant.” Id. at p 4, l. 1
(emphasis added).
29

U.S. Patent No. 8,835,460
b.

comprising discrete liquid droplets
Ross_GB further teaches that its fentanyl formulation is “preferably

administered sublingually as a spray. Id. at p 3, ll. 29-30. As explained by Dr. Park,
“one of ordinary skill in the art as of the alleged effective filing date of the ’460
patent (i.e., January 25, 2006) would have understood that the spray disclosed in
Ross_GB comprises discrete liquid droplets.” Park Decl. ¶ 16. (Exh. 1002). For
example, a spray was defined prior to the alleged effecting filing date of the ‘460
patent as having discrete liquid droplets: “water or other liquid broken up into
minute droplets and blown, ejected into, or falling through the air.”8
Accordingly, “the claimed ‘sublingual formulation comprising discrete liquid
droplets’ would have been obvious over the teachings of Ross_GB.” Park Decl. ¶
16. (Exh. 1002).
c.

of an effective amount of fentanyl a free base or a pharmaceutically
acceptable salt thereof,
Ross_GB teaches that “a therapeutically effective amount of a [fentanyl]

formulation for the treatment of pain according to the invention is used.” Ross_GB,
p 8, ll. 10-11 (emphasis added). (Exh. 1003).

a pharmaceutically acceptable liquid carrier
Ross_GB teaches that the dose of the fentanyl formulation includes water as

a pharmaceutically acceptable liquid carrier:
(a) fentanyl or a pharmaceutically acceptable salt thereof;
(b) water as carrier; and
(c) a polar organic solvent in sufficient amount to enhance the
solubility of the fentanyl or pharmaceutically acceptable salt thereof in
the water. Id. at page 3, lines 21-27 (emphasis added).
e.

wherein the sublingual fentanyl formulation comprises: from about 0.001%
to about 15% by weight of fentanyl free base
Example 1 of Ross_GB teaches a fentanyl formulation of 0.028g fentanyl,

ethanol concentration is calculated to be 2.8336g ethanol/(0.028 g + 0.0177 g +
2.8336 g + 0.0531g + 4.1516g) x 100 % = 40% by weight of ethanol. This meets
the lower bound of the range recited in the claim as “about 50% by weight of
ethanol”. Park Decl. ¶ 44. (Exh. 1002).
Ross_GB teaches “[t]he concentration of polar organic solvent is in the range
preferably of between 6 and 50%”. Ross_GB, p. 5, ll. 21-22 (Exh. 1003).
Ross_GB, further teaches “[e]xamples of polar organic solvents that may be used to
enhance the solubility of fentanyl, or the physiologically acceptable salt thereof in
the water, include: lower alcohols (e.g. C2-4 alcohols) such as ethanol.” Id. at p. 5, ll.
1-3. Finally, Ross_GB teaches “[t]he preferred polar organic solvent is ethanol.” Id.
at p. 5, ll. 6-7. Accordingly, Ross_GB teaches ethanol in the amount of 50% by
weight, which is within the range of “from about 50% to about 60% by weight of
ethanol.” Park Decl. ¶ 45. (Exh. 1002).
g.

the sublingual fentanyl formulation comprises … from about 4% to about
6% by weight of propylene glycol
Ross_GB teaches that its sublingual fentanyl formulation comprises

propylene glycol:
Examples of polar organic solvents that may be used to enhance the
solubility of fentanyl, or the physiologically acceptable salt thereof in
the water, include: lower alcohols (e.g. C2-4 alcohols) such as ethanol;
lower polyols (e.g. C2-4 polyols) such as glycerol and propylene glycol.
32

U.S. Patent No. 8,835,460

Ross_GB, p. 5, ll. 1-4 (emphasis added). (Exh. 1003).
Moreover, Ross_GB mentions a second time that its fentanyl formulation includes
propylene glycol: “[s]uitable moisturizing agents include, for example, the polar
organic solvents such as glycols, especially propylene glycol.” Id. at p. 7, ll. 11-14
(emphasis added).
In addition, the ‘862 patent teaches a buccal spray comprising propylene
glycol in a broad range of 2% to 30% by weight. ’862 patent 4:63. (Exh. 1004) As
explained by Dr. Park, “[t]he range of propylene glycol taught by the ‘862 patent
encompasses the claimed range of about 4% to about 6% by weight of propylene
glycol.” Park Decl. ¶47 (Exh. 1002). Moreover, the ‘862 patent also teaches a
buccal spray comprising propylene glycol of 7.28% by weight. ’862 patent 4:47
(Exh. 1004). As also explained by Dr. Park, “[t]his percentage of propylene glycol
meets the upper bound of the range recited in claim 2 of the ‘460 patent as about 6%
of propylene glycol.” Park Decl. ¶47 (Exh. 1002).
As further explained by Dr. Park, “[i]t would have been obvious to use the
range of propylene glycol by weight that is taught by the ‘862 patent in the fentanyl
formulation taught by Ross_GB.” Id. at ¶ 48. Ross_GB specifically calls for an
amount of polar organic solvent to “enhance the solubility of fentanyl . . .”
Ross_GB, p. 3, ll. 26-27. (Exh. 1003). Ross_GB indicates that “the formulations are
well tolerated when administered to sensitive sublingual mucosa and the sublingual

33

U.S. Patent No. 8,835,460

spray administration will result in rapid onset of the therapeutic effect of fentanyl”
and specifically identifies propylene glycol. Id. at ll. 30-32. Thus, as explained by
Dr. Park, “[o]ne skilled in the art would look to the teaching of the ‘862 patent as it
is a buccal spray for the administration of a medication that is ‘used in emergencies
when the medication should be fast acting.’”9 As further explained by Dr. Park,
“[o]ne skilled in the art would adjust and optimize the amount of propylene glycol to
account for the solubility of the drug substance as a matter of routine. Id. at ¶ 48.
The identification of the claimed range of “about 4% to 6% by weight of
propylene glycol” is nothing more than “the optimization of a range or other variable
within the claims that flows from the ‘normal desire of scientists or artisans to
improve upon what is already generally known.’” Pfizer, Inc. v Apotex, 480 F.3d
1348, 1369 (Fed. Cir. 2007) citing In re Peterson, 315 F.3d 1325, 1330
(Fed.Cir.2003) (determining where in a disclosed set of percentage ranges the
optimum combination of percentages lies is prima facie obvious). As concluded by
Dr. Park, “Accordingly it would be obvious to arrive at the claimed range based on
the teaching of Ross_GB in combination with the ‘862 patent.” Park Decl. ¶ 49.
(Exh. 1002).

U.S. Patent No. 8,835,460
h. said droplets having a mean diameter of at least about 10 microns.

Like Ross_GB, the ‘496 publication teaches a fentanyl formulation: “[t]wo
formulations containing fentanyl citrate were prepared...” ’496 Publication, ¶
[0041]. (Exh. 1005).
The ‘496 publication also teaches that its fentanyl formulation is administered
in liquid droplets “sized within the range of about 1 to 200 microns, more preferably
within the range of 10-100 microns.” Id. at ¶ [0019]. As explained by Dr. Park, “[a]
droplet within the preferred range of 10 to 100 microns clearly has a mean diameter
of at least about 10 microns recited in claim 2 of the ‘460 patent.” Park Decl. ¶ 50.
(Exh. 1002).
As further explained by Dr. Park, “[i]t would have been obvious to have a
fentanyl formulation with a discrete liquid droplet having a mean diameter of at least
about 10 microns in light of the teachings of Ross_GB, the ‘862 patent and the ‘496
publication. The ‘496 publication, like Ross_GB, teaches a fentanyl formulation.”
Id. at ¶ 51. The ‘496 publication also teaches “a decreased droplet size translates to
a higher surface area to be absorbed by the mucosa of the intra-oral cavity.” ’496
publication, ¶ [0031]. (Exh. 1005). Accordingly, as indicated by Dr. Park, “one of
ordinary skill in the art would have been motivated to combine the teachings of the
‘496 publication with the teachings of Ross_GB.” Id.
Moreover, as explained by Dr. Park, “[o]ne aspect of the administration of a

35

U.S. Patent No. 8,835,460

drug is to achieve a small droplet size so as to eliminate or decrease the discomfort
felt by a patient in receiving the drug.” Id. at ¶52. Accordingly, “one of ordinary
skill in the art would have been motivated to combine the fentanyl teachings of
Ross_GB with the small droplet size of the ‘496 publication to eliminate or
decrease any discomfort to the patient from administration of the drug.” Id.
3.

Independent Claim 3

Claim 3 is directed to a non-propellant sublingual fentanyl formulation
comprising discrete liquid droplets of an effective amount of fentanyl . . . in a
pharmaceutically acceptable liquid carrier. The sublingual fentanyl formulation
consists essentially of: from about 0.001% to about 15% by weight fentanyl free
base; from about 50% to about 60% by weight of ethanol; and from about 1% to
about 30% by weight of propylene glycol. The droplets have a mean diameter of
at least about 10 microns.
4.

The Prior Art And Its Comparison To Claim 3

As explained in detail below, claim 3 would have been obvious to one of
ordinary skill in the art in light of the teachings of Ross_GB, the ‘862 patent and the
‘496 Publication.. Park Decl. ¶ 53. (Exh. 1002).
a.

A non-propellant sublingual fentanyl formulation
Analysis of this element is provided above at § IV.B.2.a.

of an effective amount of fentanyl a free base or a pharmaceutically
acceptable salt thereof,
Analysis of this element is provided above at § IV.B.2.c.

d.

a pharmaceutically acceptable liquid carrier
Analysis of this element is provided above at § IV.B.2.d.

e.

wherein the sublingual fentanyl formulation consists essentially of: from
about 0.001% to about 15% by weight of fentanyl free base
Example 1 of Ross_GB teaches a fentanyl formulation of 0.028g fentanyl,

0.0177g saccharin, 2.8336g ethanol, 0.0531g menthol, and 4.1516g citrate buffer.
Id. at p. 11, ll. 1-9. As explained by Dr. Park, “[b]ased on this disclosure, the
fentanyl concentration is calculated to be 0.028g fentanyl / (0.028 g + 0.0177 g +
2.8336 g + 0.0531 g + 4.1516 g) x 100% = 0.395% by weight of fentanyl, which is
within the claimed range of 0.001% to 15% by weight of fentanyl.” Park Decl. ¶
58. (Exh. 1002). Further, as explained by Dr. Park, “Ross_GB does not require any
component that would interfere or prevent the fentanyl formulation from the
formation of droplets in the recited diameter range.” Id.
f.

the sublingual fentanyl formulation consists essentially of … from about
50% to about 60% by weight of ethanol
Analysis of this element is provided above at § IV.D.2.f.
37

U.S. Patent No. 8,835,460

In addition, as explained by Dr. Park, “Ross_GB does not require any
component that would interfere or prevent the fentanyl formulation from the
formation of droplets in the recited diameter range.” Id. at ¶ 59.
g.

the sublingual fentanyl formulation consists essentially of … from about
1% to about 30% by weight of propylene glycol
Ross_GB teaches that its sublingual fentanyl formulation comprises

propylene glycol:
Examples of polar organic solvents that may be used to enhance the
solubility of fentanyl, or the physiologically acceptable salt thereof in
the water, include: lower alcohols (e.g. C2-4 alcohols) such as ethanol;
lower polyols (e.g. C2-4 polyols) such as glycerol and propylene glycol.
Ross_GB, p. 5, ll. 1-4 (emphasis added). (Exh. 1003).
Moreover, Ross_GB mentions a second time that its fentanyl formulation includes
propylene glycol: “[s]uitable moisturizing agents include, for example, the polar
organic solvents such as glycols, especially propylene glycol.” Id. at p. 7, ll. 11-14
(emphasis added).
In addition, the ‘862 patent teaches a buccal spray comprising propylene
glycol in the range of 2% to 30% by weight. The ’862 patent 4:63. (Exh. 1004). As
explained by Dr. Park, “[t]he range of propylene glycol taught by the ‘862 patent is
within, and is substantially the same as, the claimed range of about 1% to about 30%
by weight of propylene glycol.” Park Decl. ¶ 60. (Exh. 1002).

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U.S. Patent No. 8,835,460

As further explained by Dr. Park, “[i]t would have been obvious to use the
range of propylene glycol by weight that is taught by the ‘862 patent in the fentanyl
formulation taught by Ross_GB.” Id. at ¶ 61. Ross_GB specifically calls for an
amount of polar organic solvent to “enhance the solubility of fentanyl . . .”
Ross_GB, p. 3, ll. 26-27. (Exh. 1003). Ross_GB indicates that “the formulations are
well tolerated when administered to sensitive sublingual mucosa and the sublingual
spray administration will result in rapid onset of the therapeutic effect of fentanyl”
and specifically identifies propylene glycol. Id. at ll. 30-32. Thus, as explained by
Dr. Park, “[o]ne skilled in the art would look to the teaching of the ‘862 patent as it
is a buccal spray for the administration of a medication that is ‘used in emergencies
when the medication should be fast acting.’”10 As further explained by Dr. Park,
“[o]ne skilled in the art would adjust and optimize the amount of propylene glycol to
account for the solubility of the drug substance as a matter of routine. Id.
Furthermore, as explained by Dr. Park, “neither Ross_GB nor the ‘862 patent
requires any component that would interfere or prevent the fentanyl formulation
from the formation of droplets in the recited diameter range.” Id. at ¶ 61.
Accordingly it would be obvious to arrive at the claimed range based on the
10

teaching of Ross_GB in combination with the ‘862 patent.” Id. at ¶ 62.
h. said droplets having a mean diameter of at least about 10 microns.

Analysis of this element is provided above at § IV.B.2.h.
C. Ground 3 -- Claims 1, 4 and 5 Are Unpatentable As Obvious Over
Ross_GB, In View Of The ’150 Patent
As explained above (§ IV.A.), Ross_GB (Exh. 1003) teaches all the
elements of claims 1, 4 and 5 of the ‘460 patent except for specifically identifying
the mean droplet diameter. As further explained above in § IV.A the‘496
publication (Exh. 1005) teaches the claimed droplet diameter; § IV.A also explains
how it would have been obvious to one skilled in the art to combine the teaching of
Ross_GB with the teaching of the ‘496 publication to arrive at claims 1, 4 and 5 of
the ‘460 patent.
As explained in detail below, the ‘150 patent (Exh. 1007) also teaches the
claimed droplet diameter. In addition, it would have been obvious to one skilled in
the art combine the teaching of ‘150 patent with Ross_GB in the same manner as
that of the ‘496 publication to arrive at claims 1, 4 and 5 of the ‘460 patent.
Accordingly, in the analysis below, the detailed explanation of how Ross_GB
teaches the elements of claims 1, 4 and 5 is not repeated but is instead referenced
to the prior section.
1.

Independent Claim 1

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U.S. Patent No. 8,835,460

Claim 1 is directed to a sublingual formulation comprising discrete liquid
droplets of an effective amount of fentanyl . . . and a pharmaceutically
acceptable liquid carrier. The droplets have a mean diameter of from about 30
to about 70 microns.
2.

The Prior Art And Its Comparison To Claim 1

As explained in detail below, claim 1 would have been obvious to one of
ordinary skill in the art in light of the teachings of Ross_GB and the ‘150 patent.
Park Decl. ¶ 64. (Exh. 1002).
a.

of an effective amount of fentanyl or a fentanyl derivative selected from the
group consisting of sufentanil, carfentanil, lofentanil and alfatenil, a free
base or a pharmaceutically acceptable salt thereof,
Analysis of this element is provided above at § IV.A.2.b.

c.

in a pharmaceutically acceptable liquid carrier
Analysis of this element is provided above at § IV.A.2.c.

d.

said droplets having a mean diameter of from about 30 to about 70 microns
The ‘150 patent teaches “that by using a pump spray with their formulations

they are able to produce a spray in which the particles have a mean aerodynamic
particle size of between 15 and 45 microns, more particularly between 20 and 40

41

U.S. Patent No. 8,835,460

microns and an average of about 33 microns.” ‘The 150 patent 4:46-52. (Exh.
1007). The ‘150 patent further teaches that “in contrast to the propellant driven
system, a pump spray could deliver an aerosol plume in which the particle size
could be controlled to generate a particle size of between 20 and 40 microns (thus
maximizing the amount of material hitting the sublingual/buccal mucosa and thus
the amount of cannabinoids that can be absorbed).” Id. at 13:50-55. As explained
by Dr. Park, “[t]he mean particle size between 15 and 45 overlaps the claimed
range of about 30 microns to about 70 microns recited in claim 1 of the ‘460
patent. Moreover, the average “of about 33 microns” is within the claimed range.”
Park Decl. ¶ 66. (Exh. 1002). Accordingly “the claimed “said droplets having a
mean diameter of from about 30 to about 70 microns” is disclosed by the teachings
of the ‘150 patent.” Id.
As further explained by Dr. Park, “[i]t would have been obvious to have a
fentanyl formulation with a discrete liquid droplet with a mean diameter of from
about 30 to about 70 microns in light of the teachings of Ross_GB and the ‘150
patent. The ‘150 patent, like Ross_GB, teaches a pump spray mechanism for
administering droplets sublingually. The ‘150 patent also teaches a particle size of
between 20 and 40 microns maximizes the amount of material hitting the
sublingual mucosa and thus maximizes the amount of [drug] that can be absorbed.”
Id. at ¶67. Accordingly, as indicated by Dr. Park, “one of ordinary skill in the art

42

U.S. Patent No. 8,835,460

would have been motivated to combine the teachings of the ‘150 patent with the
teachings of Ross_GB.” Id.
Moreover, as explained by Dr. Park, “[o]ne aspect of the administration of a
drug is to achieve a small droplet size so as to eliminate or decrease the discomfort
felt by a patient in receiving the drug.” Id. at ¶68. Accordingly, “one of ordinary
skill in the art would have been motivated to combine the fentanyl teachings of
Ross_GB with the small droplet size of the ‘150 patent to eliminate or decrease
any discomfort to the patient from administration of the drug.” Id.
3.

Independent Claim 4

Claim 4 is directed to a multi-dose device for sublingual administration of a
drug. The device comprises a reservoir containing the liquid formulation
comprising fentanyl . . . and a pharmaceutically acceptable liquid carrier. The
device has an actuator which when actuated delivers therapeutically effective dose
of the liquid formulation in the form of liquid droplets having a mean diameter of
from about 30 to about 70 microns.
4.

The Prior Art And Its Comparison To Claim 4

As explained in detail below, claim 4 would have been obvious to one of
ordinary skill in the art in light of the teachings of Ross_GB, and the ’150 patent.
Park Decl. ¶ 69. (Exh. 1002).
a.

a multi-dose device for sublingual administration of a drug

43

U.S. Patent No. 8,835,460

Analysis of this element is provided above at § IV.A.4.a.
b.

a reservoir containing the liquid formulation
Analysis of this element is provided above at § IV.A.4.b.

c.

comprising fentanyl, or a fentanyl derivative selected from the group
consisting of sufentanil, carfentanil, lofentanil and alfatenil, a free base or
a pharmaceutically acceptable salt thereof,
Analysis of this element is provided above at § IV.A.4.c.

d.

in a pharmaceutically acceptable liquid carrier;
Analysis of this element is provided above at § IV.A.4.d.

e.

the device having an actuator
Analysis of this element is provided above at § IV.A.4.e.

f.

which when actuated delivers a therapeutically effective dose of the liquid
formulation
Analysis of this element is provided above at § IV.A.4.f.

g.

in the form of liquid droplets
Analysis of this element is provided above at § IV.A.4.g.

h. having a mean diameter of from about 30 to about 70 microns

Analysis of this element (including the combination of Ross_GB, and the
’150 patent) is provided above at § IV.C.2.d.
5.

Dependent Claim 5
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U.S. Patent No. 8,835,460

Claim 5 depends from independent claim 1 and is directed to a method of
treating pain comprising sublingually administering an effective amount of the
sublingual formulation according to claim 1 to a human patient experiencing pain.
That is, claim 5 requires the same fentanyl sublingual formulation of claim 1 except
that it recites the method steps of administering an effective amount of the
formulation to a human patient experiencing pain.
6.

The Prior Art And Its Comparison To Claim 5

As explained in detail below, claim 5 would have been obvious to one of
ordinary skill in the art in light of the teachings of Ross_GB, and the ’150 patent.
Park Decl. ¶ 72. (Exh. 1002).
a.

A method of treating pain comprising
Analysis of this element is provided above at § IV.A.6.a.

b.

sublingually administering an effective amount of the sublingual
formulation according to claim 1
The analysis of the sublingual formulation according to Claim 1 is provided

above at § IV.C.2.
Analysis of the remainder of the element is provided above at § IV.A.6.b.
c.

to a human patient experiencing pain.
Analysis of this element is provided above at § IV.A.6.c.

D. Ground 4 -- Claims 2 And 3 Are Unpatentable As Obvious Over
45

U.S. Patent No. 8,835,460

Ross_GB, In View Of The ‘862 Patent, And The ‘150 Patent.
As explained above (§ IV.B.), the combination of Ross_GB (Exh. 1003) and
‘862 patent (Exh. 1004) teach all the elements of claims 2 and 3 of the ‘460 patent
except for specifically identifying the mean droplet diameter. As further explained
above in § IV.B the‘496 publication (Exh. 1005) teaches the claimed droplet
diameter; § IV.B also explains how it would have been obvious to one skilled in
the art to combine the teaching of Ross_GB and the ‘862 patent with the teaching
of the‘496 publication to arrive at claims 2 and 3 of the ‘460 patent.
As explained in detail below, the ‘150 patent (Exh. 1007) also teaches the
claimed droplet diameter. In addition, it would have been obvious to one skilled in
the art combine the teaching of ‘150 patent with Ross_GB and the ‘862 patent in
the same manner as that of the ‘496 publication to arrive at claims 1, 4 and 5 of the
‘460 patent. Accordingly, in the analysis below, the detailed explanation of how
Ross_GB teaches the elements of claims 2 and 3 is not repeated but is instead
referenced to the detailed explanation in the prior section.
1.

Independent Claim 2

Claim 2 is directed to a non-propellant sublingual fentanyl formulation
comprising discrete liquid droplets of an effective amount of fentanyl . . . in a
pharmaceutically acceptable liquid carrier. The sublingual fentanyl formulation
comprises: from about 0.001% to about 15% by weight fentanyl free base; from

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U.S. Patent No. 8,835,460

about 50% to about 60% by weight of ethanol; and from about 4% to about 6%
by weight of propylene glycol. The droplets have a mean diameter of at least
about 10 microns.
2.

The Prior Art And Its Comparison To Claim 2

As explained in detail below, claim 2 would have been obvious to one of
ordinary skill in the art in light of the teachings of Ross_GB, the ‘862 patent and the
‘150 patent. Park Decl. ¶ 74. (Exh. 1002).
a.

A non-propellant sublingual fentanyl formulation
Analysis of this element is provided above at § IV.B.2.a.

of an effective amount of fentanyl a free base or a pharmaceutically
acceptable salt thereof,
Analysis of this element is provided above at § IV.B.2.c.

d.

a pharmaceutically acceptable liquid carrier
Analysis of this element is provided above at § IV.B.2.d.

e.

wherein the sublingual fentanyl formulation comprises: from about 0.001%
to about 15% by weight of fentanyl free base
Analysis of this element is provided above at § IV.B.2.e.

47

U.S. Patent No. 8,835,460
f.

the sublingual fentanyl formulation comprises … from about 50% to about
60% by weight of ethanol
Analysis of this element is provided above at § IV.B.2.f.

g.

the sublingual fentanyl formulation comprises … from about 4% to about
6% by weight of propylene glycol
Analysis of this element is provided above at § IV.B.2.g.

h. said droplets having a mean diameter of at least about 10 microns.

The ‘150 patent teaches “that by using a pump spray with their formulations
they are able to produce a spray in which the particles have a mean aerodynamic
particle size of between 15 and 45 microns, more particularly between 20 and 40
microns and an average of about 33 microns.” ‘150 patent 4:46-52. (Exh. 1007).
The ‘150 patent further teaches that “in contrast to the propellant driven system, a
pump spray could deliver an aerosol plume in which the particle size could be
controlled to generate a particle size of between 20 and 40 microns (thus
maximizing the amount of material hitting the sublingual/buccal mucosa and thus
the amount of cannabinoids that can be absorbed).” Id. at 13:50-55. As explained
by Dr. Park, “[t]he mean particle size between 15 and 45 clearly has a mean
diameter of at least about 10 microns recited in claim 2 of the ‘460 patent.” Park
Decl. ¶ 76. (Exh. 1002).
As further explained by Dr. Park, “[i]t would have been obvious to have a
fentanyl formulation with a discrete liquid droplet having a mean diameter of at least
48

U.S. Patent No. 8,835,460

about 10 microns in light of the teachings of Ross_GB, the ‘862 patent and the ‘150
patent. The ‘150 patent, like Ross_GB, teaches a pump spray mechanism for
administering droplets sublingually. The ‘150 patent also teaches a particle size of
between 20 and 40 microns maximizes the amount of material hitting the
sublingual mucosa and thus maximizes the amount of [drug] that can be absorbed.
Id. at ¶77. Accordingly, as indicated by Dr. Park, “one of ordinary skill in the art
would have been motivated to combine the teachings of the ‘150 patent with the
teachings of Ross_GB.” Id.
Moreover, as explained by Dr. Park, “[o]ne aspect of the administration of a
drug is to achieve a small droplet size so as to eliminate or decrease the discomfort
felt by a patient in receiving the drug.” Id. at ¶78. Accordingly, “one of ordinary
skill in the art would have been motivated to combine the fentanyl teachings of
Ross_GB with the small droplet size of the ‘150 patent to eliminate or decrease
any discomfort to the patient from administration of the drug.” Id.
3.

Independent Claim 3

Claim 3 is directed to a non-propellant sublingual fentanyl formulation
comprising discrete liquid droplets of an effective amount of fentanyl . . . in a
pharmaceutically acceptable liquid carrier. The sublingual fentanyl formulation
consists essentially of: from about 0.001% to about 15% by weight fentanyl free
base; from about 50% to about 60% by weight of ethanol; and from about 1% to

49

U.S. Patent No. 8,835,460

about 30% by weight of propylene glycol. The droplets have a mean diameter of
at least about 10 microns.
4.

The Prior Art And Its Comparison To Claim 3

As explained in detail below, claim 3 would have been obvious to one of
ordinary skill in the art in light of the teachings of Ross_GB, the ‘862 patent and the
‘150 patent. Decl. ¶ 79. (Exh. 1002).
a.

A non-propellant sublingual fentanyl formulation
Analysis of this element is provided above at § IV.B.4.a.

of an effective amount of fentanyl a free base or a pharmaceutically
acceptable salt thereof,
Analysis of this element is provided above at § IV.B.4.c.

d.

a pharmaceutically acceptable liquid carrier
Analysis of this element is provided above at § IV.B.4.d.

e.

wherein the sublingual fentanyl formulation consists essentially of: from
about 0.001% to about 15% by weight of fentanyl free base
Analysis of this element is provided above at § IV.B.4.e.

f.

the sublingual fentanyl formulation consists essentially of … from about
50

U.S. Patent No. 8,835,460

50% to about 60% by weight of ethanol
Analysis of this element is provided above at § IV.B.4.f.
g.

the sublingual fentanyl formulation consists essentially of … from about
1% to about 30% by weight of propylene glycol
Analysis of this element is provided above at § IV.B.4.g.

h. said droplets having a mean diameter of at least about 10 microns.

Analysis of this element is provided above at § IV.D.2.i.
VI.

CLAIMS 1, 4 and 5 ARE ANTICIPATED
“A claim is anticipated only if each and every element as set forth in the

claim is found, either expressly or inherently described, in a single prior art
reference.”Verdegaal Bros. v. Union Oil Co. of California 814 F.2d 628, 631, 2
USPQ2d 1051, 1053 (Fed. Cir. 1987).
“If the prior art discloses its own range, rather than a specific point, then the
prior art is only anticipatory if it describes the claimed range with sufficient
specificity such that a reasonable fact finder could conclude that there is no
reasonable difference in how the invention operates over the ranges. Atofina v
Great Lakes Chem. Corp.,441 F.3d 991, 999 (Fed. Cir. 2006); ClearValue, Inc. v.
Pearl River Polymers, Inc., 668 F.3d 1340, 1345 (Fed. Cir. 2012).”
A. Ground 5 -- Claims 1, 4 and 5 Are Unpatentable As Anticipated By The
’496 Publication.
1.

Independent Claim 1
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U.S. Patent No. 8,835,460

Claim 1 is directed to a sublingual formulation comprising discrete liquid
droplets of an effective amount of fentanyl . . . and a pharmaceutically
acceptable liquid carrier. The droplets have a mean diameter of from about 30
to about 70 microns.
2.

effective for the intra-oral delivery of pharmaceutical agents.” ‘496 publication, ¶
[0002]. (Exh. 1005). The ‘496 publication further teaches “[t]he term "intra -oral
cavity" refers to all areas within the mouth, including the cheeks, gums, lips, tongue,
thorax, back of the throat, and beneath the tongue.” Id. at ¶ [0019] (emphasis
added). As explained by Dr. Park, “one of ordinary skill in the art as of the alleged
effective filing date of the ’460 patent (i.e., January 25, 2006) would have
understood “beneath the tongue” to be “sublingual.” Park Decl. ¶ 83. (Exh. 1002).
Further, the ‘496 publication teaches “[t]he pump applies pressure to the formulation
disposed within the chamber and causes the formulation to move through the
actuator. The actuator is adapted to reduce the formulation into droplets capable of
forming an aerosol spray for oral administration.” ‘496 publication, ¶ [0031]. (Exh.
52

of an effective amount of fentanyl or a fentanyl derivative selected from the
group consisting of sufentanil, carfentanil, lofentanil and alfatenil, a free
base or a pharmaceutically acceptable salt thereof,
The ‘496 publication teaches, “[t]he formulation may comprise one or more

analgesics as the pharmaceutical agent. For example, nonnarcotic analgesics such
as ketorolac and salts thereof, and oxandrolone may be used, or narcotic
analgesics, such as morphine, fentanyl and salts thereof, sedative hypnotic agents,
and codeine fentanyl citrate.” ‘496 publication, ¶ [0017] (emphasis added). (Exh.
1005). The ‘496 publication further teaches, “[t]he invention provides an efficient
and convenient drug delivery method for many pharmaceutical agents that results in
rapid onset of therapeutic action, avoids the hepatic first pass effect, and reduces the
amount of drug needed for an effective doses, thus reducing the cost.” Id. at ¶ [0014]
(emphasis added).
c.

in a pharmaceutically acceptable liquid carrier
The ‘496 publication teaches “[t]ypically, the formulation will comprise an

derivatives of vitamin E, polyvinylpyrrolidone, water, and other orally-acceptable
solvents known in the field.” Id. at ¶ [0022] (emphasis added).
d.

said droplets having a mean diameter of from about 30 to about 70 microns
The ‘496 publication also teaches that its fentanyl formulation is

administered in liquid droplets “sized within the range of about 1 to 200 microns,
more preferably within the range of 10-100 microns.” Id. at ¶ [0019]. As explained
by Dr. Park, “[t]he preferred range of 10 to 100 microns encompasses the entire
claimed range of about 30 microns to about 70 microns recited in claim 1 of the
‘460 patent.” Park Decl. ¶ 21. (Exh. 1002). As further explained by Dr. Park,
“while the preferred range of the ‘496 publication is slightly broader than the
claimed range of about 30 to about 70 microns, the ‘460 patent does not identify or
suggest there is anything advantageous about the claimed range as compared to the
preferred range of the ‘496 publication..” Id. Accordingly, “there is no reasonable
difference in how the claimed range operates over the range of the ‘496
publication. Therefore, the claimed “said droplets having a mean diameter of from
about 30 to about 70 microns” is disclosed by the ‘496 publication.” Id. at ¶ 86.
3.

Independent Claim 4

Claim 4 is directed to a multi-dose device for sublingual administration of a
drug. The device comprises a reservoir containing the liquid formulation
comprising fentanyl . . . a free base or a pharmaceutically acceptable salt thereof in
54

U.S. Patent No. 8,835,460

a pharmaceutically acceptable liquid carrier. The device has an actuator which
when actuated delivers a therapeutically effective dose of the liquid formulation in
the form of liquid droplets having a mean diameter of from about 30 to about 70
microns.
4.

The Prior Art And Its Comparison To Claim 4

As explained in detail below, claim 4 is anticipated by the ’496 publication.
Id. at ¶ 87.
a.

a multi-dose device for sublingual administration of a drug
The ‘496 publication teaches “[t]he invention further relates to a system for

delivering the formulation including a mechanism for dispensing predetermined
doses of the inventive formulation intra-orally as with an aerosol or spray pump or
propellant device.” ‘496 publication, ¶ [0031] (emphasis added). (Exh. 1005).
Further the ‘496 publication teaches, “[T]his invention relates to a formulation
effective for the intra-oral delivery of pharmaceutical agents.” Id. at ¶ [0002].The
‘496 publication further teaches “[t]he term "intra -oral cavity" refers to all areas
within the mouth, including the cheeks, gums, lips, tongue, thorax, back of the
throat, and beneath the tongue.” Id. at ¶ [0019] (emphasis added). As explained
by Dr. Park, “one of ordinary skill in the art as of the alleged effective filing date
of the ’460 patent (i.e., January 24, 2006) would have understood that “beneath the
tongue” to be “sublingual.” Park Decl. ¶ 88. (Exh. 1002).

55

U.S. Patent No. 8,835,460
b.

a reservoir containing the liquid formulation
The ‘496 publication teaches, “[w]ith the pump applicators, the mechanism

will include a container or chamber coupled to a pump and actuator. The volume
of the chamber will determine the dose that is administered with each depression of
the pump. The pump applies pressure to the formulation disposed within the
chamber and causes the formulation to move through the actuator.” ’496
publication, ¶ [0031] (emphasis added). (Exh. 1005).
c.

comprising fentanyl, or a fentanyl derivative selected from the group
consisting of sufentanil, carfentanil, lofentanil and alfatenil, a free base or
a pharmaceutically acceptable salt thereof,
The ‘496 publication teaches “[t]he formulation may comprise one or more

analgesics as the pharmaceutical agent. For example, nonnarcotic analgesics such
as ketorolac and salts thereof, and oxandrolone may be used, or narcotic
analgesics, such as morphine, fentanyl and salts thereof, sedative hypnotic agents,
and codeine fentanyl citrate.” Id. at ¶ [0017] (emphasis added).
d.

in a pharmaceutically acceptable liquid carrier;
The ‘496 publication teaches “[t]ypically, the formulation will comprise an

the device having an actuator
The ‘496 publication teaches “[w]ith the pump applicators, the mechanism

will include a container or chamber coupled to a pump and actuator. The volume
of the chamber will determine the dose that is administered with each depression of
the pump. The pump applies pressure to the formulation disposed within the
chamber and causes the formulation to move through the actuator.” Id. at ¶ [0031]
(emphasis added).
f.

which when actuated delivers a therapeutically effective dose of the liquid
formulation
The ‘496 publication teaches “[t]he actuator is adapted to reduce the

formulation into droplets capable of forming an aerosol spray for oral
administration.” Id. (emphasis added.) The ‘496 publication further teaches,
“[t]he invention provides an efficient and convenient drug delivery method for
many pharmaceutical agents that results in rapid onset of therapeutic action, avoids
the hepatic first pass effect, and reduces the amount of drug needed for an effective
doses, thus reducing the cost.” Id. at ¶ [0014] (emphasis added).
g.

in the form of liquid droplets
The ‘496 publication teaches “[t]he actuator is adapted to reduce the

U.S. Patent No. 8,835,460
h. having a mean diameter of from about 30 to about 70 microns

The ‘496 publication also teaches that its fentanyl formulation is
administered in liquid droplets “sized within the range of about 1 to 200 microns,
more preferably within the range of 10-100 microns.” Id. at ¶ [0019]. As explained
by Dr. Park, “[t]he preferred range of 10 to 100 microns encompasses the entire
claimed range of about 30 microns to about 70 microns recited in claim 1 of the
‘460 patent.” Park Decl. ¶ 95. (Exh. 1002). As further explained by Dr. Park,
“while the preferred range of the ‘496 publication is slightly broader than the
claimed range of about 30 to about 70 microns, the ‘460 patent does not identify or
suggest there is anything advantageous about the claimed range as compared to the
preferred range of the ‘496 publication.” Id. Accordingly, “there is no reasonable
difference in how the claimed range operates over the range of the 496 publication.
Therefore, the claimed “said droplets having a mean diameter of from about 30 to
about 70 microns” is disclosed by the ‘496 publication.” Id.
5.

Dependent Claim 5

Claim 5 depends from independent claim 1 and is directed to a method of
treating pain comprising sublingually administering an effective amount of the
sublingual formulation according to claim 1 to a human patient experiencing pain.
That is, claim 5 requires the same fentanyl sublingual formulation of claim 1 except
that it recites the method steps of administering an effective amount of the

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U.S. Patent No. 8,835,460

formulation to a human patient experiencing pain.
6.

The Prior Art And Its Comparison To Claim 5

As explained below, claim 5 is anticipated by the ’496 publication. Id. at ¶ 96.
a.

A method of treating pain comprising
The ‘496 publication teaches, “[t]he formulation may comprise one or more

sublingually administering an effective amount of the sublingual
formulation according to claim 1
The analysis of the sublingual formulation according to Claim 1 is provided

above at § V.A.2. The ‘496 publication further teaches, “[t]he invention provides
an efficient and convenient drug delivery method for many pharmaceutical agents
that results in rapid onset of therapeutic action, avoids the hepatic first pass effect,
and reduces the amount of drug needed for an effective doses, thus reducing the
cost.” Id. at ¶ [0014] (emphasis added). The ‘496 publication further teaches,
“[t]he solution is placed within a container of a propellant dispenser and
administered orally to provide pain relief to a patient in need thereof.” Id. The
‘496 publication further teaches “[t]he term "intra -oral cavity" refers to all areas
within the mouth, including the cheeks, gums, lips, tongue, thorax, back of the
throat, and beneath the tongue.” Id. at ¶ [0019] (emphasis added). As explained

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U.S. Patent No. 8,835,460

by Dr. Park, “one of ordinary skill in the art as of the alleged effective filing date
of the ’460 patent (i.e., January 25, 2006) would have understood that “beneath the
tongue” to be “sublingual.” Park Decl. ¶ 99. (Exh. 1002).
c.

to a human patient experiencing pain.
The ‘496 publication teaches, “[t]he formulation may comprise one or more

CERTIFICATE OF SERVICE
Under 37 C.F.R. §§ 42.6(e), this is to certify that I caused a true and correct
copy of the foregoing materials:
• Petition for Inter Partes Review of U.S. Patent No. 8,486,460 Under 35
U.S.C. § 312 and 37 C.F.R. § 42.104
• Exhibits 1001-1023
• Power of Attorney
to be served via Express Mail on the following attorneys of record as listed
in PAIR:
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Date: August 24, 2015